Bilirubin-induced ER stress contributes to the inflammatory response and apoptosis in neuronal cells
Language English Country Germany Media print-electronic
Document type Journal Article
PubMed
27578021
DOI
10.1007/s00204-016-1835-3
PII: 10.1007/s00204-016-1835-3
Knihovny.cz E-resources
- Keywords
- 4-PBA, Bilirubin neurotoxicity, CHOP, ER stress, NFкB,
- MeSH
- Apoptosis MeSH
- Astrocytoma metabolism MeSH
- Bilirubin metabolism MeSH
- Cell Differentiation MeSH
- Phenylbutyrates pharmacology MeSH
- Interleukin-8 metabolism MeSH
- Caspase 3 metabolism MeSH
- Humans MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neuroblastoma metabolism MeSH
- Neurons metabolism pathology MeSH
- Endoplasmic Reticulum Stress * MeSH
- Transcription Factor CHOP genetics MeSH
- Gene Silencing MeSH
- Cell Survival MeSH
- Inflammation pathology MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- 4-phenylbutyric acid MeSH Browser
- Bilirubin MeSH
- Phenylbutyrates MeSH
- Interleukin-8 MeSH
- Caspase 3 MeSH
- Transcription Factor CHOP MeSH
Unconjugated bilirubin (UCB) in newborns may lead to bilirubin neurotoxicity. Few studies investigated the activation of endoplasmic reticulum stress (ER stress) by UCB. We performed an in vitro comparative study using undifferentiated SH-SY5Y, differentiated GI-ME-N neuronal cells and human U87 astrocytoma cells. ER stress and its contribution to inflammation and apoptosis induced by UCB were analyzed. Cytotoxicity, ER stress and inflammation were observed only in neuronal cells, despite intracellular UCB accumulation in all three cell types. UCB toxicity was enhanced in undifferentiated SH-SY5Y cells and correlated with a higher mRNA expression of pro-apoptotic CHOP. Mouse embryonic fibroblast knockout for CHOP and CHOP siRNA-silenced SH-SY5Y increased cells viability upon UCB exposure. In SH-SY5Y, ER stress inhibition by 4-phenylbutyric acid reduced UCB-induced apoptosis and decreased the cleaved forms of caspase-3 and PARP proteins. Reporter gene assay and PERK siRNA showed that IL-8 induction by UCB is transcriptionally regulated by NFкB and PERK signaling. These data suggest that ER stress has an important role in the UCB-induced inflammation and apoptosis, and that targeting ER stress may represent a potential therapeutic approach to decrease UCB-induced neurotoxicity.
References provided by Crossref.org
The Role of Bilirubin and the Other "Yellow Players" in Neurodegenerative Diseases
